Erythromycins A through D, represented by formula (I),
(I) ErythromycinR1R2A—OH—CH3B—H—CH3C—OH—HD—H—Hare well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity. For example, the compound 6-OMe erythromycin A, or clarithromycin, has found widespread use. However, even this compound is beginning to lose its effectiveness and other erythromycin derivatives having improved activity are needed. Other 6-O-substituted erythromycin compounds have also been proposed for this purpose. For example, PCT application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 6-O-methylerythromycin A derivatives. U.S. Pat. No. 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A derivatives in which the substituents are selected from alkyl, —CONH2, —CONHC(O)alkyl and —CONHSO2 alkyl. PCT application WO 97/10251, published Mar. 20, 1997, discloses 6-O-methyl 3-descladinose erythromycin derivatives. European Patent Application 596802, published May 11, 1994, discloses bicyclic 6-O-methyl-3-oxoerythromycin A derivatives.
More recently, a class of 3-O ketolide erythromycin derivatives have been disclosed in U.S. Pat. Nos. 6,147,197 and 5,635,485. Representative lead compounds in this class include, for example ABT-773 disclosed in U.S. Pat. No. 6,147,197 and telithromycin disclosed in U.S. Pat. No. 5,635,485. The structures of these compounds are as follows:
Other modifications that have shown promise include modifications at C2, including, for example, those shown in U.S. Pat. No. 6,124,269 and International Application Publication No. WO 00/69875, the disclosures of which are incorporated herein by reference.
U.S. Pat. Nos. 5,635,485 and 6,100,404 (the disclosures of which are incorporated herein by reference) disclose ketolide derivatives of formula (I):

Presented herein are novel substituted pyridyl ketolide derivatives. The inventors have unexpectedly discovered that substituted pyridine side chains impart improved pharmacokinetic properties relative to the unsubstituted pyridyl ketolide derivatives, thus providing a better therapeutic index and better dosing regimen.
There exists a continuing medical need to identify new ketolide derivatives that possess improved antibacterial activity, less potential for developing resistance, activity against Gram-negative bacteria, increased selectivity against target microorganisms, as well as a better safety profile. In an effort to address that need, the inventors herein have prepared chemical derivatives of ketolides to obtain analogs having modified and/or improved pharmacokinetic profiles over ketolide compounds known in the art.